Raising the Bar: Expanding Expectations in HIV Therapy

1
Raising the Bar Expanding Expectationsin HIV
Therapy

• Jennifer Hoy

2
An Era of Change

• Many new treatment options for the naïve and
  experienced patients
• When
• What
• Head to head studies of IAS guidelinerecommended
  boosted PIs
• Optimal combinations of new and existing drugs
  and classes
• Undetectable is the goal for both naïve and
  treatment-experienced patients

3
First-line Therapy Fine-tuning Treatment
Decisionsin an Era of Choice

• Sharon Walmsley

4
Current Guidelines for ARV Naïve Individuals

• When to start HAART
• In the CD4 range 200-350 cells/mL (most
  resource-rich countries)
• lt200 cells/mL (resource limited settings WHO
  guidelines)
• Based on observational studies and expert
  opinionno randomized evidence

5
CD4 Counts Are Low at Start of HAART
Egger M, 14th CROI 2007. Abstract 62. ART Cohort
Collaboration. http//www.art-cohort-collaboration
.org.
6
Early HAART Confers a Survival Advantage

• HIV Outpatient Study (HOPS) cohort
• gt7,800 patients prospectively followed for 8 years

60
Mortality
48
Opportunistic Infections
50
40
26
26
Incidence per 1000 person-yrs
30
22
16
20
12
10
8
5
10
2
0
0-49
50-199
200-349
350-499
500
Pre-HAART CD4 count (cells/mm3)
Lichtenstein, 13th CROI 2006. Abstract 769.
7
Higher CD4 at HAART Initiation is Related to
Decreased Drug Toxicity

• HIV Outpatient Study (HOPS) cohort
• gt7,800 patients prospectively followed for 8
  years

Renal Insufficiency
Peripheral Neuropathy
Lipoatrophy
1.2
1.0

Plt.05
0.8




Patients
0.6



0.4
0.2
0
lt200
lt349
lt499
gt500
lt200
lt349
lt499
gt500
lt200
lt349
lt499
gt500
CD4 cell count (cells/mm3)
Lichtenstein, 13th CROI 2006. Abstract 769.
8
The Risk of Early HAARTIncreased Relative Risk
of Myocardial Infarction
DAD Study
RR adjusted by year of PI 1.15 1.0621.25
RR adjusted by year of NNRTI 0.94 0.741.19
8
6
4
MIs per 1000 PYFU (95CI)
2
0
None
lt1
1-2
2-3
3-4
4-5
5-6
gt6
Friis-Møller N et al, 13th CROI 2006. Abstract
144.
9
Once You Start It Is Not SMART to STOP
SMART study
Treatment interruption group vs viral
suppression group.
El-Sadr WM et al. N Engl J Med.
20063552283-2296.
10
What Should We Start Treatment With?

• Guidelines recommend lt10 different initial
  regimens

Number of Different First-line Regimens Usedto
Treat 90 of Patients, 20032005
3
47
59
3
11
Egger M, 14th CROI 2007. Abstract 62. ART Cohort
Collaboration. http//www.art-cohort-collaboration
.org.
11
IAS Guidelines for First-line Therapy

• Initial regimen should include 2 NRTIs and
  either a PI/r or an NNRTI

PI/r
NRTI
NNRTI
TDF FTC ZDV 3TC ABC 3TC
EFV (or NVP)
LPV/r SQV/r ATV/r FPV/r
FTC can be used in place of 3TC and vice
versa. Avoid in pregnant women and women with
significant pregnancy potential. Hammer SM et al.
JAMA. 2006296827-843.
12
Choosing an NRTI Background
TDF FTC ZDV 3TC ABC 3TC
Pairing choices
NRTI
FTC can be used in place of 3TC and vice versa.
Hammer SM et al. JAMA. 2006296827-843.
13
What Should the Third Partner Be?
OR
PI/r
NNRTI

• Transmitted drug resistance
• Genetic barrier to resistance
• Cross-class resistance
• Treatment-limiting adverse events
• Metabolic abnormalities
• Lipodystrophy
• Adherence
• Choices

14
Transmitted Resistance in Naïve Patients A
Global Study
WATCH Worldwide Analysis of resistance
Transmission over time of Chronically and acute
infected HIV-1 patients
PI
NRTI
NNRTI
8
6
Resistance per class
4
2
0
NorthAmerica
Europe
S/SE Asia
Africa
LatinAmerica
East Asia
WORLDWIDE
Bowles E et al, 1st HIV Transmission Workshop
2006.
15
PI/r Is Less Affected by Suboptimal Adherence
Hazard Ratio for Viral Failure in Patients with
lt95 Adherence
PI
NNRTI
Boosted PI
0
0.5
1.0
1.5
2.0
2.5
3.0

• HOMER cohort study
• 1,634 patients (19962003) with undetectable VL
• Adherence calculated and stratified 95 or lt95
  based on pharmacy scripts filled
• 606 patients (37) experienced breakthrough
  viremia

Gross R et al, 13th CROI 2006. Abstract 533.
16
Randomized Controlled Comparative TrialsACTG 5142
LPV/r SGC 533/133 mg bid EFV 600 mg qd
LPV/r SGC 400/100 mg bid 2 NRTI
EFV 600 mg qd 2 NRTI
Riddler et al, WAC 2006. Abstract THLB0204.
17
EFV Superior Virologic Suppression But Inferior
CD4 Cell Increase
HIV RNA lt50 copies/mL
Median CD4 Cell Increase
100
285
300
268
89
83
240
77
75
200
Patients
Cells/mL
50
100
25
0
0
LPV/r
LPV/r
EFV
LPV/r
LPV/r
EFV
EFV
NRTIs
NRTIs
EFV
NRTIs
NRTIs
96 weeks on study
P .003 for LPV/r NRTIs vs EFV NRTIs. P
.01 for LPV/r NRTIs and LPV/r EFV vs EFV
NRTIs. Riddler S et al, IAC 2006. Abstract
THLB0204.
18
Resistance at Virologic Failure
Some genotype assays pending. 30N, 32I, 33F,
46I, 47A/V, 48V, 50L/V, 82A/F/L/S/T, 84V, 90M.
Riddler S et al, IAC 2006. Abstract THLB0204.
19
ACTG 5142 Lipoatrophy (gt20 Loss Extremity Fat)
50
42
40
32
27
30
Lipoatrophy (gt20 loss)
17
20
9
9
10
0
EFV
LPV
LPVEFV
d4T
ZDV
TDF
96 weeks on study
Haubrich R et al, 14th CROI 2007. Abstract 38.
20
ACTG 5142 Lipid Profile
70
62
57
60
46
50
44
40
33
Median increase (mg/dL)
32
26
30
22
19
16
20
9
8
10
0
Total Cholesterol
Triglycerides
HDL Cholesterol
Non-HDL Cholesterol
LPV/r EFV
LPV/r 2 NRTI
EFV 2 NRTI
Haubrich R et al, 14th CROI 2007. Abstract 38.
21
Not All PIs Have the Same Impact on Blood Sugar
Regulation
1Noor MA, et al. AIDS. 2004182137-2144. 2Slim J
et al. 8th International Congress on Drug Therapy
in HIV Infection. Glasgow, 2006. Abstract PL2.5.
3Noor MA, et al. AIDS. 20062018131821. 4Lee
GA, et al. Clin Infect Dis. 200643658660.
5Noor MA, et al. AIDS. 200216F1F8. 6Dube MP,
et al. Clin Infect Dis. 200235475-481.
22
Summary

• ARV therapy continues to improve
• Most patients initiate treatment with 2 NRTIs
  and EFV or a PI/r
• Treatment choices are driven by
• Efficacy and durability
• Adherence
• Short and long term toxicity
• Resistance at baseline and at failure
• There is no one choice for all patients

23
(No Transcript)